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Title: Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia
Author: Giménez Carabaza, Neus
Martínez Trillos, Alejandra
Montraveta, Arnau
López-Guerra, Mónica
Rosich, Laia
Nadeu, Ferran
Valero, Juan G.
Aymerich Gregorio, Marta
Magnano, Laura
Rozman, María
Matutes, Estella
Delgado, Julio (Delgado González)
Baumann, Tycho
Gine, Eva
González, Marcos
Alcoceba, Miguel
Terol, Maria José
Navarro, Blanca
Colado, Enrique
Payer, Ángel R.
Puente, Xose S.
López-Otin, Carlos
López Guillermo, Armando
Campo Güerri, Elias
Colomer Pujol, Dolors
Villamor i Casas, Neus
Keywords: Leucèmia limfocítica crònica
Mutació (Biologia)
Chronic lymphocytic leukemia
Mutation (Biology)
Issue Date: Mar-2019
Publisher: Ferrata Storti Foundation
Abstract: Mutations in genes of the RAS-BRAF-MAPK-ERK pathwayhave not been fully explored in patients with chronic lym-phocytic leukemia. We, therefore, analyzed the clinical andbiological characteristics of chronic lymphocytic leukemia patientswith mutations in this pathway and investigated thein vitroresponseof primary cells to BRAF and ERK inhibitors. Putative damaging muta-tions were found in 25 of 452 patients (5.5%). Among these, BRAFwas mutated in nine patients (2.0%), genes upstream of BRAF(KITLG,KIT, PTPN11, GNB1, KRASand NRAS) were mutated in 12 patients(2.6%), and genes downstream of BRAF(MAPK2K1, MAPK2K2, andMAPK1) were mutated in five patients (1.1%). The most frequentmutations were missense, subclonal and mutually exclusive. Patientswith these mutations more frequently had increased lactate dehydro-genase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12and unmutated immunoglobulin heavy-chain variable region genesand had a worse 5-year time to first treatment (hazard ratio 1.8,P=0.025). Gene expression analysis showed upregulation of genes ofthe MAPK pathway in the group carrying RAS-BRAF-MAPK-ERKpathway mutations. The BRAF inhibitors vemurafenib and dabrafenibwere not able to inhibit phosphorylation of ERK, the downstreameffector of the pathway, in primary cells. In contrast, ulixertinib, apan-ERK inhibitor, decreased phospho-ERK levels. In conclusion,although larger series of patients are needed to corroborate these find-ings, our results suggest that the RAS-BRAF-MAPK-ERK pathway isone of the core cellular processes affected by novel mutations inchronic lymphocytic leukemia, is associated with adverse clinical fea-tures and could be pharmacologically inhibited.
Note: Reproducció del document publicat a:
It is part of: Haematologica, 2019, vol. 104, num. 3, p. 576-586
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ISSN: 0390-6078
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Fonaments Clínics)

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